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Genome Replication-Incompetent Sendai Virus Vaccine Vector Against Respiratory Viral Infections That Is Capable of Eliciting a Broad Spectrum of Specific Immune Response

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Sendai Virus Vector

Abstract

Vaccines have proven to be the most effective measure against infectious diseases. However, not every infectious disease can be prevented by vaccination at the present time. For some diseases, new vaccination strategies have to be developed because classical approaches have not been successful. Viral vectors represent one novel strategy to develop specifically designed recombinant vaccines. Many vaccines have to be applied to certain risk groups among the population that represent large parts of the population, such as infants, children, the elderly, or people with a compromised immune system. Because of the altered competence of the immune system of such individuals, the safety issue is of prime importance. In the case of viral vector-based vaccines, safety will be increased if they are rendered fully replication deficient because replication deficiency does not allow vector spreading and persistence within the vaccinees or mutation toward a more pathogenic variant. In the present chapter we first take up, as an example, respiratory syncytial virus (RSV) to discuss the past problems and future options in its vaccine development. We then illustrate our efforts to develop a genome replication-deficient Sendai virus (SeV) vaccine vector. Three essential prerequisites had to be met by such a vector: (1) complete genome replication deficiency while still being able to efficiently express the inserted vaccine antigen genes; (2) stability of viral genome and encoded trans-genes; and (3) production of the replication-deficient vector stock to a sufficiently high titer in a trans-complementing cell culture system.

Replication deficiency of SeV vector could be achieved via different modifications of components involved in the viral replication complex that consists of the viral N, P, and L proteins. The viral polymerase can operate in two ways: transcription to enable gene expression and genome replication to generate progeny genomes. The difficulty was to keep the polymerase efficiently performing transcription while its replication activity was completely switched off. Rational design and reverse genetics allowed us to analyze various SeV variants with mutations in the N, P, and L genes. Finally, uncoupling of transcription from replication could be achieved via deletion of an N-terminal part of the P protein that encodes amino acids 2 to 77. Using this vector backbone, the first prototype divalent vaccine against RSV and parainfluenza type-3 virus was developed. The vaccine showed a sufficiently high production titer and high genetic stability. It proved to be fully replication deficient while still expressing the Sendai viral and transgenes at significant levels and was able to elicit a broad spectrum of humoral and cellular immune responses in animals. This preclinical proof-of-concept should lay the ground to use this novel vector platform for specific developments of vaccines with an enhanced safety profile.

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Authors and Affiliations

  1. AmVac Research GmbH, Lochhamer Strasse 29a, 82152, Martinsried, Germany

    Marian Wiegand

  2. Department of Molecular Virology, Max Planck Institute of Biochemistry, 82152, Martinsried, Germany

    Wolfgang J. Neubert

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  1. Marian Wiegand
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  2. Wolfgang J. Neubert
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Correspondence to Marian Wiegand .

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  1. CRNID, RIKEN, Tokyo, Tokyo, Japan

    Yoshiyuki Nagai

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Wiegand, M., Neubert, W.J. (2013). Genome Replication-Incompetent Sendai Virus Vaccine Vector Against Respiratory Viral Infections That Is Capable of Eliciting a Broad Spectrum of Specific Immune Response. In: Nagai, Y. (eds) Sendai Virus Vector. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54556-9_4

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